Ferroptotic- and non-ferroptotic mechanisms associated with doxorubicin-induced male reproductive dysfunction

Abstract

Despite the effectiveness of doxorubicin as a chemotherapeutic agent, it exerts toxicity on non-target organs, including the male reproductive organs. This review synthesizes current evidence on both ferroptotic and non-ferroptotic mechanisms underlying doxorubicin (DOX)-induced male reproductive dysfunction. DOX disrupts testicular function by inducing oxidative stress, lipid peroxidation, mitochondrial dysfunction, and apoptosis, particularly in Leydig, Sertoli, and spermatogenic cells. These effects result in reduced testosterone production, impaired spermatogenesis, and poor semen quality. Additionally, DOX alters the hypothalamic-pituitary-gonadal (HPG) axis and downregulates key enzymes involved in steroidogenesis, exacerbating hormonal imbalances and infertility risks. Emerging research highlights ferroptosis, iron-dependent cell death, as a major contributor to DOX-induced testicular damage, with evidence showing that antioxidant agents like melatonin and zinc oxide nanoparticles may offer protective effects. In addition, the results of this review reveal the necessity of investigating the potential of interventional strategies. This research highlights the need for integrative care approaches prioritizing cancer management and fertility preservation. This review aims to inform healthcare providers, patients, and policymakers about the significant consequences of doxorubicin therapy and open new therapeutic horizons for adjuvant therapies.